A single nucleotide polymorphism of Leu412Phe (TLR3 L412F), a toll-like receptor 3, may pose a significant risk factor for acute exacerbations contributing to worse prognosis in individuals with idiopathic pulmonary fibrosis (IPF), according to results of a new study published in the American Journal of Respiratory Critical Care Medicine.

The authors explained the research of McElroy and colleagues who made the original observation that TLR3 L412F was related to worse outcomes in patients with IPF. McElroy and colleagues investigated whether this single nucleotide polymorphism corresponded to the patient’s response to infections, contributing to mortality in IPF.

McElroy and colleagues recruited 228 patients with IPF, 107 of whom were either 412F heterozygous or homozygous. Following nasopharyngeal lavages for all 228 patients with IPF, the investigators observed specific combinations of viruses and bacteria present in the samples, in particular influenza virus and Staphylococcus aureus or rhinovirus and Streptococcus pneumoniae.

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Following a bronchoalveolar lavage of the patients with IPF, S pneumoniae and S aureus bacterial species predominated in those with the 412F heterozygous variant compared with Prevotella which predominated in those with wild type L412. These analyses implied altered regulation of the lung microbiome due to the TLR3 L412F polymorphism.

Patients with the 412F variant exhibited significantly increased mortality related to acute exacerbations compared to patients with wild-type L412 IPF. Patients with the 412F polymorphism demonstrated an impaired host immune response to bacterial and viral infections, indicated by differing responses to various toll-like receptor pathogen-associated molecular patterns in addition to reduced transcription of interferon-stimulated genes.

The authors identified a future course of study, focusing on the anti-infective activity of alveolar macrophages and airway epithelial cells. These cells both stand as the first line of defense against pulmonary infections.

“The study can be considered a significant step forward in the understanding of some of those pathogenic mechanisms that contribute to explain the occurrence of [acute exacerbations] in IPF patients,” the authors concluded.


Vancheri C, Luppi F. Identifying the risk of acute exacerbation in idiopathic pulmonary fibrosis: another step forward. Am J Respir Crit Care Med. Published online January 25, 2022. doi:10.1164/rccm.202110-2244ED